Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation

Leventhal, Joseph R.; Abécassis, Michaël; Miller, Joshua; Gallon, Lorenzo; Ravindra, Kadiyala V.; Tollerud, David J.; King, Bradley; Elliott, Mary Jane; Herzig, Geoffrey P.; Herzig, Roger H.; Ildstad, Suzanne T.

doi:10.1126/scitranslmed.3003509

Cited by 384 publications

(344 citation statements)

References 41 publications

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“…Hematopoietic stem cells were the first cell type assessed in patients for the induction of chimerism and subsequent allograft tolerance [82], but this approach is associated with graft versus host disease (GVHD), humoral rejection and graft loss in some cases [83]. Recent studies have shown that the injection of "facilitating cells" [84] or mesenchymal stem cells [85,86] in combination with hematopoietic stem cells could protect recipients from GVHD and allow the long-term induction of chimerism and tolerance. Given their immunomodulatory properties [87], mesenchymal stem cells are a promising tool to induce allograft-specific tolerance and potentially the subsequent withdrawal of immunosuppressive therapy.…”

Section: Strategies To Limit Renal Ischemia-reperfusion Injuries and mentioning

confidence: 99%

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

et al. 2014

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In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemiareperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.

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Section: Strategies To Limit Renal Ischemia-reperfusion Injuries and mentioning

confidence: 99%

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

et al. 2014

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“…The groups from Northwestern and University of Louisville reported a novel approach to augment donor stem cell engraftment in conjunction with renal transplant (Leventhal et al 2012). They make use of a bone marrow-derived CD8 þ , TCR -"facilitator cell" population that promotes the engraftment of allogeneic hematopoietic stem cells in animal models without observed GVHD (Kaufman et al 1994).…”

Section: Mixed Chimerismmentioning

confidence: 99%

“…They make use of a bone marrow-derived CD8 þ , TCR -"facilitator cell" population that promotes the engraftment of allogeneic hematopoietic stem cells in animal models without observed GVHD (Kaufman et al 1994). To date, data on 15 patients undergoing their protocol have been reported (Leventhal et al 2012(Leventhal et al , 2013. Recipients undergo a "low-intensity" conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total-body irradiation.…”

Section: Mixed Chimerismmentioning

confidence: 99%

Tolerance--Is It Worth It?

Finger

Strom

Matas

2013

Cold Spring Harbor Perspectives in Medicine

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We are entering an exciting time in the study of immunologic tolerance. Several cellular and molecular strategies have been developed that show promise in nonhuman transplant models and these approaches are just now appearing in clinical trials. Tolerance strategies that prevent immune rejection and obviate the need for immunosuppressive medications (with inherent risk of cancer, infection, and organ toxicity) would improve both graft and patient survival. Each tolerance protocol brings its own set of associated risks. As the results of these trials become available, we must continue to evaluate their successes and failures. The balance of these outcomes will help us answer the question: "Tolerance-Is it worth it?"WHAT IS TOLERANCE?

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“…As the majority of transplant recipients are well into adulthood, treatments that preserve or even enhance thymic function are clinically attractive. In recent years, two clinical studies (16,17) using HLA-mismatched transplants have demonstrated stable graft survival without maintenance immunosuppression, but only in a small group of relatively young patients (median age 41.5 in (16) and 25 in (17). Therefore, tolerance induction protocols clearly need to be rigorously tested in the aged setting for clinical translation to be successful.…”

Section: Introductionmentioning

confidence: 99%

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Morison

Homann

Hammett

et al. 2014

American Journal of Transplantation

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y Co-senior authors.Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing longterm graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system.

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Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation

Cited by 384 publications

References 41 publications

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

Tolerance--Is It Worth It?

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

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